{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:23:44Z","timestamp":1793838224566,"version":"4.6.1"},"reference-count":42,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,12,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Antibodies against the chemokine platelet factor 4 (PF4) occur often, but only those that activate platelets induce severe prothrombotic disorders with associated thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is the prototypic anti-PF4 disorder, mediated by strong activation of platelets through their Fc\u03b3IIa (immunoglobulin G [IgG]) receptors (Fc\u03b3RIIa). Concomitant pancellular activation (monocytes, neutrophils, endothelium) triggers thromboinflammation with a high risk for venous and arterial thrombosis. The classic concept of HIT is that anti-PF4\/heparin IgG, recognizing antigen sites on (cationic) PF4 that form in the presence of (anionic) heparin, constitute the heparin-dependent antibodies that cause HIT. Accordingly, HIT is managed by anticoagulation with a nonheparin anticoagulant. In 2021, adenovirus vector COVID-19 vaccines triggered the rare adverse effect \u201cvaccine-induced immune thrombotic thrombocytopenia\u201d (VITT), also caused by anti-PF4 IgG. VITT is a predominantly heparin-independent platelet-activating disorder that requires both therapeutic-dose anticoagulation and inhibition of Fc\u03b3RIIa-mediated platelet activation by high-dose intravenous immunoglobulin (IVIG). HIT and VITT antibodies bind to different epitopes on PF4; new immunoassays can differentiate between these distinct HIT-like and VITT-like antibodies. These studies indicate that (1) severe, atypical presentations of HIT (\u201cautoimmune HIT\u201d) are associated with both HIT-like (heparin-dependent) and VITT-like (heparin-independent) anti-PF4 antibodies; (2) in some patients with severe acute (and sometimes chronic, recurrent) thrombosis, VITT-like antibodies can be identified independent of proximate heparin exposure or vaccination. We propose to classify anti-PF4 antibodies as type 1 (nonpathogenic, non\u2013 platelet activating), type 2 (heparin dependent, platelet activating), and type 3 (heparin independent, platelet activating). A key concept is that type 3 antibodies (autoimmune HIT, VITT) require anticoagulation plus an adjunct treatment, namely high-dose IVIG, to deescalate the severe anti-PF4 IgG-mediated hypercoagulability state.<\/jats:p>","DOI":"10.1182\/hematology.2023000503","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T10:05:59Z","timestamp":1702029959000},"page":"1-10","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":64,"title":["Thrombotic anti-PF4 immune disorders: HIT, VITT, and beyond"],"prefix":"10.1182","volume":"2023","author":[{"given":"Andreas","family":"Greinacher","sequence":"first","affiliation":[{"name":"1 Institut f\u00fcr Transfusionsmedizin, Universit\u00e4tsmedizin Greifswald, Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore E.","family":"Warkentin","sequence":"additional","affiliation":[{"name":"2 Department of Pathology and Molecular Medicine and Department of Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"issue":"August","key":"2023120815052167700_hem2023000503C1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.thromres.2021.05.018","article-title":"Spontaneous HIT syndrome: knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia","volume":"204","author":"Warkentin","year":"2021","journal-title":"Thromb Res"},{"issue":"9","key":"2023120815052167700_hem2023000503C2","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1161\/ATVBAHA.122.317162","article-title":"Thromboinflammation: from atherosclerosis to COVID-19","volume":"42","author":"Wagner","year":"2022","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"11","key":"2023120815052167700_hem2023000503C3","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1111\/jth.14264","article-title":"Heparin-induced thrombocytopenia-associated thrombosis: from arterial to venous to venous limb gangrene","volume":"16","author":"Warkentin","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"22","key":"2023120815052167700_hem2023000503C4","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.1182\/bloodadvances.2018024489","article-title":"American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia","volume":"2","author":"Cuker","year":"2018","journal-title":"Blood Adv"},{"issue":"8","key":"2023120815052167700_hem2023000503C5","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1080\/17474086.2019.1636645","article-title":"High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review","volume":"12","author":"Warkentin","year":"2019","journal-title":"Expert Rev Hematol"},{"issue":"7","key":"2023120815052167700_hem2023000503C6","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1056\/NEJMra1316259","article-title":"Ischemic limb gangrene with pulses","volume":"373","author":"Warkentin","year":"2015","journal-title":"N Engl J Med"},{"issue":"22","key":"2023120815052167700_hem2023000503C7","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1056\/NEJMoa2104840","article-title":"Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination","volume":"384","author":"Greinacher","year":"2021","journal-title":"N Engl J Med"},{"issue":"22","key":"2023120815052167700_hem2023000503C8","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1056\/NEJMoa2104882","article-title":"Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination","volume":"384","author":"Schultz","year":"2021","journal-title":"N Engl J Med"},{"issue":"23","key":"2023120815052167700_hem2023000503C9","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1056\/NEJMoa2105385","article-title":"Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination","volume":"384","author":"Scully","year":"2021","journal-title":"N Engl J Med"},{"issue":"7873","key":"2023120815052167700_hem2023000503C10","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41586-021-03744-4","article-title":"Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia","volume":"596","author":"Huynh","year":"2021","journal-title":"Nature"},{"key":"2023120815052167700_hem2023000503C11","unstructured":"World Health Organization. Guidance for clinical case management of thrombosis with thrombocytopenia syndrome (TTS) following vaccination to prevent coronavirus disease (COVID-19). https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/366678\/9789240061989-eng.pdf. 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